Many different materials have been investigated to resist non-specific protein adsorption. Chemistries utilized for this purpose include, but are not limited to: polyethers (e.g., polyethylene glycol), polysaccharides such as dextran, hydrophilic polymers such as polyvinylpyrrolidone or hydroxyethylmethacrylate, heparin, intramolecular zwitterions or mixed charge materials, and hydrogen bond accepting groups such as those described in U.S. Pat. No. 7,276,286. The ability of these materials in preventing protein adsorption varies greatly between the chemistries. Of these materials, only a few resist fouling to the degree required for short-term in vivo application. However, the few materials appropriate for short-term application, when used for longer periods of time in complex media or in vivo, exhibit significant fouling or material degradation, making them unsuitable for long-term applications. Furthermore, surfaces coated with materials that resist in vivo degradation are often susceptible to a noticeable decrease in fouling resistance over time.
WO 2007/02493 describes grafting sulfobetaine and carboxybetaine from self-assembled monolayers on gold substrates or from silyl groups on glass substrates using atom transfer radical polymerization (ATRP). Gold and glass are not appropriate substrates for many medical devices used in vivo. Self-assembled monolayers, such as thiol-based monolayers, may be unstable since the thiol group is not stably bound to the substrate.
U.S. Pat. No. 6,358,557 to Wang et al. describes the graft polymerization of substrate surfaces, but not with a high density of a highly non-fouling polymeric material. A thermal initiator is used to initiate polymerization, typically at temperatures greater than 85° C. Such temperatures are generally not suitable for many medical devices, such as thin-walled polyurethane catheters. Further, the “salt out” method described is generally not suitable for grafting polymers such as zwitterionic polymers.
Jian et al., Colloids and Surfaces B: Biointerfaces 28, 1-9 (2003) describes the surface modification of segmented poly(ether urethane) by grafting sulf ammonium zwitterionic monomer, but not with a high density of non-fouling material. The resulting materials are not sufficiently non-fouling to be useful in medical device applications.
It is therefore an object of the invention to provide non-fouling polymeric coatings for various substrates, such as polymers and metal oxides, which retain their activity in the presence of blood proteins and/or in vivo due to improved molecular structures, and allow for cooperative action of immobilized agents and protein resistant chemistries to resist non-specific protein adsorption.
It is further an object of the present invention to provide non-fouling compositions containing a high density of non-fouling polymeric material and/or wherein the inter-polymer chain distance of the non-fouling polymeric materials decreases the penetration of fouling molecules into the non-fouling coating.
It is further an embodiment of the invention to provide graft-from methods of coating surfaces formed of biomaterials wherein the grafting is initiated from within the biomaterials to provide materials with a high density and stability of non-fouling polymer.